Cell adhesion and migration contribute to normal processes such as differentiation, embryonic development, and wound healing as well as to the progression of diseases and pathological conditions that can result from either acute or chronic exposure to environmental toxicants, such as cancer and inflammatory responses. Key mechanistic steps in these processes involve the interactions of extracellular glycoproteins--such as fibronectin, laminin, and collagens--with specific adhesive receptors, the best characterized of which are the integrins, a family of heterodimeric complexes consisting of an alpha subunit and a beta subunit. Integrins are highly regulated receptors that can exist in either an active or inactive state.[unreadable] [unreadable] Selectins are vascular cell-cell adhesion molecules involved in leukocyte trafficking, inflammation, thrombosis, autoimmunity and cancer. Accumulation of leukocytes at sites of inflammation is initiated by selectins that mediate the capturing and rolling of leukocytes on endothelium. Three major members of the selectin family have been identified: L-selectin, E-selectin and P-selectin. L-Selectin is constitutively expressed on leukocytes. P-and E-selectins are expressed on activated endothelial cells in response to microenvirnomental stimuli. P-selectin is also expressed on thrombin-activated platelets. All three members of the selectin family, E-, L-, and P-selectin can bind to human tumor cells and cancer-derived cell line. [unreadable] [unreadable] Our research has focused recently on the possible role of inflammatory cues in activation of integrin-mediated tumor cell migration and invasion. As a model system, we are examining the ability of one selectin, P-selectin, to trigger integrin-mediated adhesion and migration of cultured human tumor cells. [unreadable] [unreadable] We have found that P-selectin could induce up to a 2-fold increase in attachment and spreading of Colo-320 human carcolon carcinoma cells specifically to fibronectin substrates. Activation of integrin-mediated adhesion by P-selectin binding to Colo-320 tumor cells was concentration- and time-dependent, with maximal activation being reached with approximately 0.01 mg/ml P-selectin chimera and in less than approximately 30 minutes. This adhesion was mediated by the fibronectin-specific alpha5-beta1 integrin. Activation was also transient and was not due to increased expression of cell surface alpha5 or beta1 integrin. The P-selectin receptor on Colo-320 cells has been identified as a cell surface form of nucleolin. Nucleolin is tyrosine phosphorylated as a result of nucleolin binding.[unreadable] [unreadable] We also found that P-selectin binding can induce signal transduction in the form of a concomitant increase of phosphatidylinositol-3 kinase (PI-3 kinase) and p38 MAP kinase activities. Furthermore, inhibiting PI-3 kinase blocked P-selectin-activated cell attachment suggesting that this pathway is involved in integrin activation. In contrast specific p38 inhibitors had no effect on P-selectin-activated attachment to fibronectin but did inhibit the more complicated process of cell spreading. P-selectin binding to Colo-320 cells also results in the formation of a signaling complex that contains PI-3 kinase, p38 and phosphorylated nucleolin form a signaling complex in a P-selectin dependent manner, as judged by co-immunoprecipitation experiments and confocal immunofluorescence microscopy.